Traditionally scientists looked for a single gene that causes a disease, but you wanted to study hypertension, which is much more complex. Why not study a more cooperative disease?

This is one of the big challenges in science, to figure out how to have the most impact on the most important problems. Twenty years ago tools were starting to emerge from the human genome project that gave us hope that we would be able to start understanding not just rare diseases that are in the field of, typically, medical genetics, but that we might start having an impact on common diseases too. I was attracted to cardiovascular disease initially because it is the single largest cause of death worldwide. In particular, I was interested in investigating hypertension, a major risk factor for cardiovascular disease that affects one billion people around the world.

What was your strategy?

At the time, it was recognized that blood pressure is not like simple disorders where there are likely to be single genes that have big effects that are common in the population. So we took a page from simple studies in model organisms. For decades we’ve done experiments in model organisms like fruit flies where we’ve taken complex problems and done mutagenesis on the flies to make mutations, and then look at which mutations have really large effects on traits that we’re interested in. We obviously can’t do mutagenesis in humans, but we can take advantage of the fact that there are 13 billion copies of the human genome walking around the planet—six-and-a-half billion people with two copies of each gene.

We reasoned that if we could cast our net broadly enough, we ought to be able to identify extreme outliers in the population who have either extraordinarily high blood pressure or life threatening blood pressure at very young ages. If these turn out to be due to mutations in single genes, we ought to be able to identify the underlying mutations that cause these traits.

And when you gathered a large enough sample of these extraordinary people, what did you learn?

I think the most impressive finding is that, despite the incredible complexity of blood pressure regulation, the mutations that we’ve identified — and we now have mutations in 10 genes that will dramatically raise blood pressure and another 10 that will dramatically lower blood pressure — that these aren’t distributed throughout the physiologic landscape, but instead they converge on a single final common pathway and that is the pathway that regulates salt re-absorption by the kidney.

How has this changed the way physicians treat high blood pressure?

Our work has demonstrated the fundamental importance of reduction in salt balance as a primary goal of therapy. The national recommendations now reflect this in recommending salt reduction as a key goal of therapy. In addition, our studies have identified several therapeutic targets that might lead to improved treatment of this common disease; these are under development.

Interestingly, we also found that patients who have an inherited defect that causes them to lose salt all the time also have a very powerful behavioral drive to eat more salt. Children who can’t hang onto salt normally in the kidney will tell you fascinating things, like their favorite beverage is pickle juice, or they like to eat lemons covered in salt. So, extrapolating these observations to the treatment of patients with hypertension, we now recognize that in addition to giving them a single agent that reduces salt balance, we need to give them agents that reduce the drive to eat more salt as well.

Because we’re talking about a hereditary disorder, does that make patients particularly eager to collaborate with you?

Absolutely. I think this is one of the lessons that we have learned time and again. The part that has impressed me greatly is not that the patients expect there is going to be any direct benefit to them, but they recognize that their families have problems that could advance the understanding of a particular disorder and might ultimately improve healthcare in the future. We quite commonly are invited to family reunions to study family members.

You’ve met some fascinating people. Talk about the man who couldn’t float.

This patient came to our attention because of a motor vehicle accident on a Saturday night and a very astute resident at the hospital. If you have a motor vehicle accident and you’re brought to the emergency room, you virtually always have x-rays taken of your cervical spine to rule out a life-threatening fracture. The resident saw there was no fracture, but he was very concerned because the patient’s bones appeared to be the densest he had ever seen and he was concerned that he might have some serious underlying disease.

(Dr.) Karl Insogna at the Bone Center at Yale measured the patient’s bone density and said only one in many billion people would have such high bone density. The patient had no complaints at all except that he and many of his family members sank when they tried to swim. We found their bodies don’t simply slow down the loss of bone, they actually are making more bone all the time.

Lynn Boyden in the laboratory identified the underlying mutation, which identified a new signaling pathway in the normal regulation of bone formation. This finding has focused further investigation in the pharmaceutical industry to attempt to develop new medicines that could mimic the effect of these mutations. The goal is to increase the rate of deposition of bone to prevent the development of osteoporosis and to reverse its effects.

You are increasingly looking at renal disease. Please explain why this is so timely.

Kidney disease is where we were with high blood pressure 10 years ago. There are hundreds of thousands of Americans on dialysis now because their kidneys have failed. Yet we know very little about the primary causes. We know there are risk factors: diabetes, high blood pressure and inherited contributions. What has changed from when we started in high blood pressure is the tools have gotten progressively better as time has gone on. The complete sequence of the human genome has been finished; we now know all of the common variations in the human genome sequence. Now we can start to look both for common variants that contribute to kidney disease, as well as rare variants that contribute to this trait. I’m quite optimistic that in the next several years we will start to identify some of the inherited contributions to this trait and that these will ultimately lead to new therapies that will prevent this disease.

How do you think genetics is going to fundamentally change medicine within the next decade?

If you look at where we started 10 years ago and where we’ve come in just that time period, I think it’s safe to say that virtually every area of medicine has been drastically changed in its fundamental understanding of disease pathogenesis. This cuts across every disease, from Alzheimer’s disease, to diabetes, to high blood pressure, to cholesterol, to cancer. We have made fundamental advances in understanding basic pathways that are contributing to disease predisposition, but we’ve been doing this with extremely blunt tools. We have been able to find the genes that have whopping effects in rare individuals, but our tools are now getting sharp enough to enable us to start to identify what are the genes that are predisposing to disease in the general population.

I think there will be two general contributions emerging over the next five years: one, starting already to happen, will be finding the common variations that have fairly modest — but on the population level, substantial — contributions to the risk of disease. And then I think increasingly over the next several years we will have the ability to not just look at a large number of common variants in the general population, but to actually be able to re-sequence all of the genes in a single individual or in cohorts of individuals. This will really start to have a major impact on the way we both diagnose predisposition as well as start to think about how can we actually impact the treatment of these disorders.

There is a very big gap between knowing the cause of disease and being able to treat it. What genetics now has the promise to do is to tell you not just that this is something that might work, but it’s something that has an extremely high likelihood of success and will not fail because of adverse therapeutic effect, something that has been a major problem in the pharmaceutical industry as well. This holds enormous process for streamlining the process of disease understanding, leading all the way to new therapeutics.

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